Abstract
Meprinα, an astacin-type metalloprotease is overexpressed in colorectal cancer cells and is secreted in a non-polarized fashion, leading to the accumulation of meprinα in the tumor stroma. The transition from normal colonocytes to colorectal cancer correlates with increased meprinα activity at primary tumor sites. A role for meprinα in invasion and metastatic dissemination is supported by its pro-angiogenic and pro-migratory activity. In the present study, we provide evidence for a meprinα-mediated transactivation of the EGFR signaling pathway and suggest that this mechanism is involved in colorectal cancer progression. Using alkaline phosphatase-tagged EGFR ligands and an ELISA assay, we demonstrate that meprinα is capable of shedding epidermal growth factor (EGF) and transforming growth factor-α (TGFα) from the plasma membrane. Shedding was abrogated using actinonin, an inhibitor for meprinα. The physiological effects of meprinα-mediated shedding of EGF and TGFα were investigated with human colorectal adenocarcinoma cells (Caco-2). Proteolytically active meprinα leads to an increase in EGFR and ERK1/2 phosphorylation and subsequently enhances cell proliferation and migration. In conclusion, the implication of meprinα in the EGFR/MAPK signaling pathway indicates a role of meprinα in colorectal cancer progression.
Highlights
epidermal growth factor receptor (EGFR) signaling pathway activation is a crucial step in colorectal cancer tumor progression
Using alkaline phosphatase-tagged EGFR ligands and an ELISA assay, we demonstrate that meprin␣ is capable of shedding epidermal growth factor (EGF) and transforming growth factor-␣ (TGF␣) from the plasma membrane
EGF and TGF␣ Are Shed by Meprin␣—To investigate the role of meprin␣ in ectodomain shedding of EGF and TGF␣, a cell-based assay using alkaline phosphatase (AP)-tagged EGFR ligands was used
Summary
EGFR signaling pathway activation is a crucial step in colorectal cancer tumor progression. Meprin␣, an astacin-type metalloprotease is overexpressed in colorectal cancer cells and is secreted in a non-polarized fashion, leading to the accumulation of meprin␣ in the tumor stroma. Two other groups discovered the same metalloprotease in the early 1980s: Sterchi et al, in 1982, described the enzyme PABA peptide hydrolase (PPH) in microvillar membranes of human small intestinal epithelial cells [25], and Kenny et al, in 1987, found the endopeptidase-2 in the microvillar membrane of proximal epithelial cells of rat kidney [26] This metalloprotease is known as “meprin.” There are two evolutionary related isoforms: Meprin␣ and meprin. For the first time we demonstrate that meprin␣ is able to shed EGF from the plasma membrane, resulting in the transactivation of EGFR signaling pathway and enhancement of Caco-2 cell proliferation and migration.
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